NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This ...study aimed to investigate the role of intermediate‐length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate‐length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho‐alpha‐synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate‐length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate‐length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate‐length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182–187
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is ...overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied.
We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models.
Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT.
Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Amyloid-β (Aβ) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer's disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that ...approximately half of the Aβ produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aβ clearance remain largely unknown. The kidney is thought to be responsible for Aβ clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aβ in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on Aβ clearance via the kidney were assessed. We detected Aβ in the kidneys and urine of both humans and animals and found that the Aβ level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aβ deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain Aβ levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aβ from the blood, suggesting that facilitation of Aβ clearance via the kidney represents a novel potential therapeutic approach for AD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Single-cell RNA sequencing (scRNA-seq) technologies are poised to reshape the current cell-type classification system. However, a transcriptome-based single-cell atlas has not been achieved for ...complex mammalian systems. Here, we developed Microwell-seq, a high-throughput and low-cost scRNA-seq platform using simple, inexpensive devices. Using Microwell-seq, we analyzed more than 400,000 single cells covering all of the major mouse organs and constructed a basic scheme for a mouse cell atlas (MCA). We reveal a single-cell hierarchy for many tissues that have not been well characterized previously. We built a web-based “single-cell MCA analysis” pipeline that accurately defines cell types based on single-cell digital expression. Our study demonstrates the wide applicability of the Microwell-seq technology and MCA resource.
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•Development of Microwell-seq, a high-throughput and low-cost scRNA-seq platform•Construction of a single-cell mouse cell atlas (scMCA) covering major cell types•Characterization of cellular heterogeneity with minimal batch effect•Characterization of cross-tissue cellular network at the single-cell level
Development of Microwell-seq allows construction of a mouse cell atlas at the single-cell level with a high-throughput and low-cost platform.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Carboxy-terminus of Hsc70-interacting protein (CHIP) functions both as a molecular co-chaperone and ubiquitin E3 ligase playing a critical role in modulating the degradation of numerous ...chaperone-bound proteins. To date, it has been implicated in the regulation of numerous biological functions, including misfolded-protein refolding, autophagy, immunity, and necroptosis. Moreover, the ubiquitous expression of CHIP in the central nervous system suggests that it may be implicated in a wide range of functions in neurological diseases. Several recent studies of our laboratory and other groups have highlighted the beneficial role of CHIP in the pathogenesis of several neurological diseases. The objective of this review is to discuss the possible molecular mechanisms that contribute to the pathogenesis of neurological diseases in which CHIP has a pivotal role, such as stroke, intracerebral hemorrhage, Alzheimer's disease, Parkinson's disease, and polyglutamine diseases; furthermore, CHIP mutations could also cause neurodegenerative diseases. Based on the available literature, CHIP overexpression could serve as a promising therapeutic target for several neurological diseases.
Brushless direct current motor is widely used in industrial production because of its simple structure, wide speed range and low noise. To improve the operation efficiency of brushless DC motor and ...reduce the production and application costs, the optimization of brushless DC motor is analyzed by introducing the JAYA algorithm. This method determines the optimal parameters of a brushless DC motor using the theory of electromagnetic structure parameter selection and efficiency calculation. The population diversity of the JAYA algorithm is improved through an empirical learning strategy, and an adaptive strategy is introduced to balance the development ability and search performance of the algorithm. This ensures population diversity and improves convergence speed. The experiment showcases that the improved JAYA algorithm has a lower rank average in unimodal function operations, demonstrating stronger local development ability and better stability. It exhibits strong search ability in many local optima of multimodal functions. Moreover, the motor's average efficiency after optimization is 94.48%. The algorithm reaches the global optimum after approximately 40 iterations and offers faster convergence speed and higher accuracy. The adaptive JAYA algorithm is stable at around 93% when the number of iterations reaches 90, with a maximum efficiency of 95.3%. It is 5-12 percentage points higher than the other three comparison algorithms. The optimal solution of the motor parameters in the adaptive JAYA algorithm is closest to the theoretical parameter optimization value, meeting both the constraints of variables and the constraints of the model. The stator diameter, tooth magnetic induction, winding current density, air gap magnetic induction, and stator yoke magnetic induction values are 201.5 mm, 1.8 T, 2.049 A/mm
, 0.63 T, and 0.91 T, respectively. The research overcomes the problem of parameter optimization in the optimization design of brushless DC motor, improving their economic value of brushless DC motor in industrial production and application.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual ...HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The traditional Chinese alcoholic beverage Baijiu is produced by spontaneous fermentation of grains under anaerobic conditions. While numerous studies have used metagenomic technology to investigate ...the microbiome of Baijiu brewing, the microbial succession mechanism of Baijiu brewing has not been fully clarified, and metagenomic strategies for microecology surveys have not been comprehensively evaluated. Using the fermentation process of strong-flavor Baijiu as a model, we compared the data for bacterial communities based on short read 16S rRNA variable regions, V3–V4, and full-length 16S regions, V1–V9, to whole metagenomic shotgun sequencing (WMS) to measure the effect of technology selection on phylogenetic and functional profiles. The results showed differences in bacterial compositions and their relation to volatiles and physicochemical variables between sequencing methods. Furthermore, the percentage of V3–V4 sequences assigned to species level was higher than the percentage of V1–V9 sequences according to SILVA taxonomy, but lower according to NCBI taxonomy (P < 0.05). In both SILVA and NCBI taxonomies, the relative abundances of bacterial communities at both the genus and family levels were more positively correlated with WMS data in the V3–V4 dataset than in the V1–V9 dataset. The WMS identified changes in abundances of multiple metabolic pathways during fermentation (P < 0.05), including “starch and sucrose metabolism,” “galactose metabolism,” and “fatty acid biosynthesis.” Although functional predictions derived from 16S data show similar patterns to WMS, most metabolic pathway changes are uncorrelated (P > 0.05). This study provided new technical and biological insights into Baijiu production that may assist in selection of methodologies for studies of fermentation systems.
•Different sequencing methods were evaluated for microbial study of Baijiu.•V1–V9 of 16S rRNA produce higher-resolution community profiles than V3–V4 in NCBI.•V3–V4 data present more similar microbial profiles to shotgun data than V1–V9.•Predictions of microbial function based on 16S data differ from actual function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Trimethylation on H3K27 (H3K27me3) mediated by Polycomb repressive complex 2 (PRC2) has been linked to embryonic stem cell (ESC) identity and pluripotency. EZH2, the catalytic subunit of PRC2, has ...been reported as the sole histone methyltransferase that methylates H3K27 and mediates transcriptional silencing. Analysis of
Ezh2
−/−
ESCs suggests existence of an additional enzyme(s) catalyzing H3K27 methylation. We have identified EZH1, a homolog of EZH2 that is physically present in a noncanonical PRC2 complex, as an H3K27 methyltransferase in vivo and in vitro. EZH1 colocalizes with the H3K27me3 mark on chromatin and preferentially preserves this mark on development-related genes in
Ezh2
−/−
ESCs. Depletion of
Ezh1 in cells lacking
Ezh2 abolishes residual methylation on H3K27 and derepresses H3K27me3 target genes, demonstrating a role of EZH1 in safeguarding ESC identity.
Ezh1 partially complements
Ezh2 in executing pluripotency during ESC differentiation, suggesting that cell-fate transitions require epigenetic specificity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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